Stress and affective dysregulation play an important role in the course of addiction to nicotine and in the course of addictive disorders in general. A better understanding of how stress and hedonic systems interact is critical to developing better treatments for these conditions. Chronic nicotine and stress may cause an overlapping network of changes in neuronal function and gene expression which over time may render the brain more vulnerable to stress, stress-induced drug craving, and drug effects. The research goals of this Mentored Clinical Scientist Career Development Award are to understand relationships between changes in neuronal activity and gene expression induced by stress and by nicotine, to locate these changes precisely in neuroanatomical circuits, and to correlate such changes with steps in drug-taking in a mouse model. The application emphasizes understanding anatomical patterns because such an approach could suggest new brain locations and neurochemical targets for novel treatments for nicotine addiction and addictive disorders in general. The first aim of the program is to understand how chronic exposure to stress alters responses to nicotine at the level of neuronal activation. The second aim is to learn in greater detail where and to what extent nicotine and stress act in similar ways in the brain, focusing on patterns of gene expression. The final portion of the program seeks to understand how stress may potentiate nicotine's ability to regulate gene expression in the brain in ways that are relevant to the addictive process. Three distinguished mentors will be responsible for the career development of the candidate during the award period - Dr. Loma Role, an expert in molecular neurobiology and biology of cholinergic systems; Dr. Eliot Gardner, an expert in the biology of addictions; and Dr. Alexander Glassman, who provides clinical expertise in nicotine addiction and mood disorders. The candidate has also arranged collaborations with other experts who will add to the training component and help accomplish the research. These are Dr. Patrick Hof, an expert neuroanatomist; Dr. David Talmage and Dr. Etienne Sibille, experts in molecular biology and use of microarrays; Dr. Jay Gingrich, an expert behavioral neuroscientist; and Dr. Frances Levin, an additional clinical expert on addiction studies. The program has been designed to culminate in the candidate establishing an independent research program.